Existing fluid responsiveness studies using the mini-fluid challenge may be misleading:Methodological considerations and simulations

BACKGROUND: The mini-fluid challenge (MFC) is a clinical concept of predicting fluid responsiveness by rapidly infusing a small amount of intravenous fluids, typically 100 ml, and systematically assessing its haemodynamic effect. The MFC method is meant to predict if a patient will respond to a subsequent, larger fluid challenge, typically another 400 ml, with a significant increase in stroke volume. METHODS: We critically evaluated the general methodology of MFC studies, with statistical considerations, secondary analysis of an existing study, and simulations. RESULTS: Secondary analysis of an existing study showed that the MFC could predict the total fluid response (MFC + 400 ml) with an area under the receiver operator characteristics curve (AUROC) of 0.92, but that the prediction was worse than random for the response to the remaining 400 ml (AUROC = 0.33). In a null simulation with no response to both the MFC and the subsequent fluid challenge, the commonly used analysis could predict fluid responsiveness with an AUROC of 0.73. CONCLUSION: Many existing MFC studies are likely overestimating the classification accuracy of the MFC. This should be considered before adopting the MFC into clinical practice. A better study design includes a second, independent measurement of stroke volume after the MFC. This measurement serves as reference for the response to the subsequent fluid challenge

Pen needle design influences ease of insertion, pain, and skin trauma in subjects with type 2 diabetes

OBJECTIVE: Pen needles used for subcutaneous injections have gradually become shorter, thinner and more thin walled, and thereby less robust to patient reuse. Thus, different needle sizes, alternative tip designs and needles resembling reuse were tested to explore how needle design influences ease of insertion, pain and skin trauma. RESEARCH DESIGN AND METHODS: 30 subjects with injection-treated type 2 diabetes and body mass index 25–35 kg/m(2) were included in the single-blinded study. Each subject received abdominal insertions with 18 different types of needles. All needles were tested twice per subject and in random order. Penetration force (PF) through the skin, pain perception on 100 mm visual analog scale, and change in skin blood perfusion (SBP) were quantified after the insertions. RESULTS: Needle diameter was positively related to PF and SBP (p<0.05) and with a positive pain trend relation. Lack of needle lubrication and small ‘needle hooks’ increased PF and SBP (p<0.05) but did not affect pain. Short-tip, obtuse needle grinds affected PF and SBP, but pain was only significantly affected in extreme cases. PF in skin and in polyurethane rubber were linearly related, and pain outcome was dependent of SBP increase. CONCLUSIONS: The shape and design of a needle and the needle tip affect ease of insertion, pain and skin trauma. Relations are seen across different data acquisition methods and across species, enabling needle performance testing outside of clinical trials. TRIAL REGISTRATION NUMBER: NCT02531776; results

Growth Histories in Bimetric Massive Gravity

We perform cosmological perturbation theory in Hassan-Rosen bimetric gravity for general homogeneous and isotropic backgrounds. In the de Sitter approximation, we obtain decoupled sets of massless and massive scalar gravitational fluctuations. Matter perturbations then evolve like in Einstein gravity. We perturb the future de Sitter regime by the ratio of matter to dark energy, producing quasi-de Sitter space. In this more general setting the massive and massless fluctuations mix. We argue that in the quasi-de Sitter regime, the growth of structure in bimetric gravity differs from that of Einstein gravity.Comment: 28 pages + appendix, 11 figure

Erratum

We acknowledge cofunding of the research from the EU ITN project SynCrop (project number 764591), appointment of Luca Mantovanelli

V-Proportion: a method based on the Voronoi diagram to study spatial relations in neuronal mosaics of the retina

The visual system plays a predominant role in the human perception. Although all components of the eye are important to perceive visual information, the retina is a fundamental part of the visual system. In this work we study the spatial relations between neuronal mosaics in the retina. These relations have shown its importance to investigate possible constraints or connectivities between different spatially colocalized populations of neurons, and to explain how visual information spreads along the layers before being sent to the brain. We introduce the V-Proportion, a method based on the Voronoi diagram to study possible spatial interactions between two neuronal mosaics. Results in simulations as well as in real data demonstrate the effectiveness of this method to detect spatial relations between neurons in different layers

Improving scientific rigour in conservation evaluations and a plea deal for transparency on potential biases

The delivery of rigorous and unbiased evidence on the effects of interventions lay at the heart of the scientific method. Here we examine scientific papers evaluating agri-environment schemes, the principal instrument to mitigate farmland biodiversity declines worldwide. Despite previous warnings about rudimentary study designs in this field, we found that the majority of studies published between 2008 and 2017 still lack robust study designs to strictly evaluate intervention effects. Potential sources of bias that arise from the correlative nature are rarely mentioned, and results are still promoted by using a causal language. This lack of robust study designs likely results from poor integration of research and policy, while the erroneous use of causal language and an unwillingness to discuss bias may stem from publication pressures. We conclude that scientific reporting and discussion of study limitations in intervention research must improve and propose some practices toward this goal

Dabigatran dual therapy versus warfarin triple therapy post-PCI in patients with atrial fibrillation and diabetes

OBJECTIVES: The aim of this study was to evaluate dabigatran dual therapy versus warfarin triple therapy in patients with or without diabetes mellitus in the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial.BACKGROUND: It is unclear whether dual therapy is as safe and efficacious as triple therapy in patients with atrial fibrillation with diabetes following percutaneous coronary intervention.METHODS: In RE-DUAL PCI, 2,725 patients with atrial fibrillation (993 with diabetes) who had undergone PCI were assigned to warfarin triple therapy (warfarin, clopidogrel or ticagrelor, and aspirin) or dabigatran dual therapy (dabigatran 110 mg or 150 mg twice daily and clopidogrel or ticagrelor). Median follow-up was 13 months. The primary outcome was the composite of major bleeding or clinically relevant nonmajor bleeding, and the main efficacy outcome was the composite of death, thromboembolic events, or unplanned revascularization.RESULTS: Among patients with diabetes, the incidence of major bleeding or clinically relevant nonmajor bleeding was 15.2% in the dabigatran 110 mg dual therapy group versus 27.5% in the warfarin triple therapy group (hazard ratio [HR]: 0.48; 95% confidence interval [CI] 0.35 to 0.67) and 23.8% in the dabigatran 150 mg dual therapy group versus 25.1% in the warfarin triple therapy group (HR: 0.87; 95% CI: 0.62 to 1.22). Risk for major bleeding or clinically relevant nonmajor bleeding was also reduced with both dabigatran doses among patients without diabetes (dabigatran 110 mg dual therapy: HR: 0.54; 95% CI: 0.42 to 0.70; dabigatran 150 mg dual therapy: HR: 0.63; 95% CI: 0.48 to 0.83). Risk for the efficacy endpoint was comparable between treatment groups for both patients with and those without diabetes. No interaction between treatment and diabetes subgroup could be observed, either for bleeding or for composite efficacy endpoints.CONCLUSIONS: In this subgroup analysis, dabigatran dual therapy had a lower risk for bleeding and a comparable rate of the efficacy endpoint compared with warfarin triple therapy in patients with atrial fibrillation with or without diabetes following percutaneous coronary intervention.</p

Identification of the estrogen receptor beta as a possible new tamoxifen-sensitive target in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype. Despite the proven efficacy of combined immunochemotherapy (R-CHOP) in the majority of patients, ~40% of DLBCL patients do not respond or will relapse and consequently have a very poor prognosis. The development of targeted therapies has not improved patient survival, underscoring the need for new treatment approaches. Using an unbiased genome-wide CD20 guilt-by-association approach in more than 1800 DLBCL patients, we previously identified the estrogen receptor beta (ERβ) as a new target in DLBCL. Here, we demonstrate that ERβ is expressed at significantly higher levels in DLBCL compared to normal B cells, and ERβ plays a role in the protection against apoptosis in DLBCL. Targeting of the ERβ with the selective estrogen receptor modulator tamoxifen reduces cell viability in all tested DLBCL cell lines. Tamoxifen-induced cell death was significantly decreased in an ERβ knock-out cell line. The activity of tamoxifen was confirmed in a xenograft human lymphoma model, as tumor growth decreased, and survival significantly improved. Finally, tamoxifen-treated breast cancer (BC) patients showed a significantly reduced risk of 38% for DLBCL compared to BC patients who did not receive tamoxifen. Our findings provide a rationale to investigate tamoxifen, a hormonal drug with a good safety profile, in DLBCL patients

Structural stigma and sexual minority men's depression and suicidality: A multilevel examination of mechanisms and mobility across 48 countries.

Sexual minority men are at greater risk of depression and suicidality than heterosexuals. Stigma, the most frequently hypothesized risk factor for this disparity, operates across socioecological levels-structural (e.g., laws), interpersonal (e.g., discrimination), and individual (e.g., self-stigma). Although the literature on stigma and mental health has focused on interpersonal and individual forms of stigma, emerging research has shown that structural stigma is also associated with adverse mental health outcomes. However, there is limited data on whether changes in structural stigma, such as when a stigmatized person moves to a lower stigma context, affect mental health, and on the mechanisms underlying this association. To address these questions, we use data from the 2017/18 European Men-who-have-sex-with-men Internet Survey (n = 123,428), which assessed mental health (i.e., Patient Health Questionnaire) and psychosocial mediators (i.e., sexual orientation concealment, internalized homonegativity, and social isolation). We linked these data to an objective indicator of structural stigma related to sexual orientation-including 15 laws and policies as well as aggregated social attitudes-in respondents' countries of origin (N = 178) and receiving countries (N = 48). Among respondents who still live in their country of birth (N = 106,883), structural stigma was related to depression and suicidality via internalized homonegativity and social isolation. Among respondents who moved from higher-to-lower structural stigma countries (n = 11,831), longer exposure to the lower structural stigma environments of their receiving countries was associated with a significantly: 1) lower risk of depression and suicidality; 2) lower odds of concealment, internalized homonegativity, and social isolation; and 3) smaller indirect effect of structural stigma on mental health through these mediators. This study provides additional evidence that stigma is a sociocultural determinant of mental health